SCIENCE CHINALife Sciences

•   REVIEW   • December 2016   Vol.59   No.12:1305–1312doi: 10.1007/s11427-016-0240-4

Mesenchymal stem cells-derived exosomal microRNAs contributeto wound inflammation

Dongdong Ti, Haojie Hao, Xiaobing Fu* & Weidong Han**

Institute of Basic Medicine, College of Life Sciences, Chinese PLA General Hospital, Beijing 100853, China

Received August 25, 2016; accepted October 16, 2016; published online November 18, 2016

Clinical and experimental studies have highlighted the significance of inflammation in coordinating wound repair andregeneration. However, it remains challenging to control the inflammatory response and tolerance at systemic levels withoutcausing toxicity to injured tissues. Mesenchymal stem cells (MSCs) possess potent immunomodulatory properties and facilitatetissue repair by releasing exosomes, which generate a suitable microenvironment for inflammatory resolution. Exosomes containseveral effective bioactive molecules and act as a cell-cell communication vehicle to influence cellular activities in recipient cells.During this process, the horizontal transfer of exosomal microRNAs (miRNAs) to acceptor cells, where they regulate targetgene expression, is of particular interest for understanding the basic biology of inflammation ablation, tissue homeostasis, anddevelopment of therapeutic approaches. In this review, we describe a signature of three specific miRNAs (miR-21, miR-146a,and miR-181) present in human umbilical cord MSC-derived exosomes (MSC-EXO) identified microarray chip analysis andfocus on the inflammatory regulatory functions of these immune-related miRNAs. We also discuss the potential mechanismscontributing to the resolution of wound inflammation and tissue healing.

microRNA, inflammation, mesenchymal stem cell, exosome

Citation: Ti, D., Hao, H., Fu, X., and Han, W. (2016). Mesenchymal stem cells-derived exosomal microRNAs contribute to wound inflammation. Sci China LifeSci 59, 1305–1312. doi: 10.1007/s11427-016-0240-4

INTRODUCTIONInflammation is an evolutionarily biophysical self-defense re-sponse of the body to harmful stimuli and aims to maintain ahomeostatic state (Kizil et al., 2015). Immune cells, mainlyresident macrophages, dendritic cells, and neutrophils, are ac-tivated during inflammation and recruited to the impaired siteto initiate the healing process by eradicating pathogens anddamaged cells. Although an acute and well-regulated inflam-matory response is typically crucial for returning cells andorganisms to homeostasis, chronic and inappropriate inflam-mation is hazardous to tissues and predisposes patients to the

*Corresponding author (email: fuxiaobing@vip.sina.com)**Corresponding author (email: hanwdrsw69@yahoo.com)

onset or progression of delayed wound healing (Sugimoto etal., 2016; Landén et al., 2016). Therefore, the regulation ofinflammation is a potential therapeutic target for interventionto reduce the risk of disease and disability.Recently, stem cell-based technologies using mesenchymal

stem cells (MSCs) have been proposed for the treatment ofinflammation-related diseases (Liu et al., 2016; Gao et al.,2016; Shen et al., 2015). MSCs are a population of self-re-newing undifferentiated adult cells that can be obtained fromdifferent tissues (bone marrow, umbilical cord, adipose, etc.)and are typically defined as plastic-adherent, fibroblast-likecells with the potential to differentiate along a distinct vari-ety of cell lineages. They can home to the injured sites, in-teract with several cells of the immune system, and modulate

The Author(s) 2016. This article is published with open access at link.springer.com    life.scichina.com    link.springer.com

the local microenvironment through their unique immunolog-ical properties. Bury et al. found that MSC grafts markedlyreduced the presence of pro-inflammatory macrophages andneutrophils, attenuated the innate inflammatory response, andfacilitated bladder tissue regeneration (Bury et al., 2015). Inaddition, administeredMSCsmay inhibit dendritic cell differ-entiation and maturation, reduce lymphocyte activities, anddecrease the cytotoxic activity of natural killer cells in acutekidney injury (De Miguel et al., 2012).Increasing evidence has suggested that MSCs secrete

exosomes as vital extracellular communicators to modulatethe proliferation, activation, and effector function of targetedcells and have therapeutic effects on wound inflammation(Fontaine et al., 2016; Ophelders et al., 2016; Nakano et al.,2016). Exosomes, which were first defined by Trams et al.,are small biological lipid membrane vesicles with diametersfor 40–100 nm (Trams et al., 1981). Researchers determinedthe exosome biogenesis process in different cell types andsuccessfully isolated these membranous bodies from diversesources, ranging from bodily fluids to the supernatants of cul-tured cells. Under physiological and pathological conditions,these vesicles are formed by inward budding of late endo-somes and then released into the extracellular environmentupon fusion with the plasma membrane (Basso and Bonetto,2016). They can shuttle biologically active molecules, suchas intact and functional microRNAs (miRNAs), messengerRNAs (mRNAs), and proteins, to targeted recipient cellsand reprogram cell behaviors (Zhou et al., 2016; Fang et al.,2016).miRNAs are highly conserved, small (19–24 nt), non-cod-

ing RNA molecules that regulate gene expression at thepost-transcriptional level by promoting the degradation orblocking of mRNA translation. It has been reported thatseveral miRNAs play crucial roles in regulating differentinflammatory responses in many tissues and affect the phe-notype and development of immune cells. Dysregulationof miR-21 or miR-181 induces a chronic inflammatorystate; this miRNA is key in controlling the balance be-tween initial pro-inflammatory and later immuno-regulatory,anti-inflammatory responses (Garo and Murugaiyan, 2016;Sun et al., 2014). As master molecular switches, miRNAsexchange bio-information between neighboring cells andare important in exosome-mediated microenvironmentalchanges (Cavalieri et al., 2016; Navakanitworakul et al.,2016). Montecalvo et al. showed that miRNAs in exosomesare remarkably stable, likely because of their unique struc-ture that protects them against harsh degrading conditions,such as low acidic pH and RNase-mediated degradation(Montecalvo et al., 2012). miRNAs transferred throughexosomes, such as miR-146a and miR-155, are expressedin a tissue- and cell type-specific manner and can alter thehost cell to evade the host’s innate immune response andinfluence their survival and activated or differentiated status

(Alexander et al., 2015). In addition, the miRNA componentof exosomes is heterogeneous and depends on the cells oforigin. Various microenvironmental factors, including cal-cium concentration and growth factors, can also influence thetransport of information by exosomes and their regulatoryproperties (Taverna et al., 2016).MSC-derived exosomes (MSC-EXO) have been proposed

as an ideal therapeutic strategy for wound inflammation.When exposed to an extremely harsh inflammatory mi-croenvironment within injured sites, engrafted stem cellsexhibit low survival rates, limiting their sustained reparativecapacity. Exosomes resist external degradation and providetarget cells with effective genetic information, and thusMSC-EXO may be non-invasive and dynamic candidates asgene therapy vectors to communicate important regulatorysignals between cells and mediate protective signals againststress in other cells during wound inflammation. miRNA“marker signatures”, which are carried and secreted byMSC-EXO, may participate in the resolution of chronicinflammation and enhance the curative effects of MSCs. Abetter understanding of the miRNA expression profiles andputative specific miRNA functions within MSC-EXO willfacilitate further development of MSC-mediated exosometherapy aimed at the modification of wound inflammation.

HOW MSCS FUNCTION IN WOUNDINFLAMMATION

Inflammation is not only an essential step of wound heal-ing but also has large impacts on the final wound outcome.If unchecked and persistent, it can lead to delayed woundsthat are characteristic of fibrosis, excessive scar formation,or inhibiting reepithelialization. Numerous basic and clini-cal data over the last decade indicate that the anti-inflamma-tory and immunomodulative properties of MSCs are partic-ularly beneficial for poor wound treatment, as they advancethe wound’s capacity to progress beyond the inflammatorystage and not transit to an impaired wound state (Gao et al.,2016; van den Akker et al., 2013). After the immunomodu-latory capacities are activated by the inflammatory microen-vironment of the wound sites, MSCs secrete different bioac-tive components, exert pleiotropic effects on immune cells atinjured sites, and play a protective role in remedying tissueinflammation and improving healing. In a mouse model ofautoimmune encephalomyelitis, MSCs effectively inhibitedTh17 cell polarization and ameliorated the development ofautoimmune responses by secreting large amounts of solubleTNF receptor to antagonize TNF-α function (Ke et al., 2016).TNF-α is considered as a major proinflammatory medium inthe promotion of Th17 cell differentiation and the pathophys-iology of autoimmune encephalomyelitis. Additionally, Xuet al. found that accelerated diabetic wound healing by MSCtreatment was associated with significantly up-regulated ex-

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pression of miR-146a and suppression of proinflammatorytarget genes expression (Xu et al., 2012). Based on these stud-ies, MSC may reprogram a well-orchestrated and proregen-erative microenvironment for inflammation adjustment theninduce functional restoration of injured tissues, which maybe primarily related to the paracrine mechanism triggered byMSCs. As active ingredients of trophic secretion by MSCs,exosomes are important regulators of cell-to-cell communi-cation for inflammatory signaling and wound repair by shut-tling functional materials such as protein and miRNAs. Stud-ies have shown that MSC-EXO significantly depressed lym-phocyte proliferation, restrained the inflammatory response,and played a cardioprotective role. A decrease in the concen-tration of exosomes, results in the slower recovery of dam-aged hearts (Teng et al., 2015). Thus, further investigationsare necessary to explain the transporter roles of MSC-EXOin wound healing and analyze the composition of exosomesto reveal their detailed mechanisms in chronic inflammation.

MIRNA EXPRESSION PATTERNS RELEASEDBY MSC-EXO

Computational and indirect evidence has indicated thatmiRNAs directly manage up to one-third of protein-codinggenes. They act as critical immune-modulators of diverseprocesses, including the differentiation and induction ofimmune cells and maintenance of cellular homeostasis andfunctions (Mehta and Baltimore, 2016). For example, pre-conditioning of MSCs triggers internal changes in cells,possibly at the post-transcriptional and/or epigenetic levels,which are responsible for subsequent gene reprogrammingor robust immune tolerance (Zhang et al., 2016; Dong etal., 2015; Aktas et al., 2016). In our previous study, wefound that lipopolysaccharide (LPS) priming can augmentthe paracrine protective ability and therapeutic potentialityof MSCs; additionally, let-7b was distinctively shuttled byLPS-pretreated MSC-derived exosomes (LPS pre-Exo), mayfunction in the balance of macrophage polarization to curechronic inflammation and enhance skin wound repair (Ti etal., 2015). MiRNAs are induced in a time-specific manner,and the resulting regulatory network is often very extensiveand complicated. Therefore, it is not surprising that miRNAsare partially taken up by MSCs as cargo in exosomes toinfluence coordinated changes in gene expression occurringduring the resolution of wound inflammation.Therefore, in order to explore whether MSC-EXO exert

the immunomodulative properties through specific miRNAs,we cultured human umbilical cord MSCs at the 4th–5th pas-sages, harvested exosomes from the supernatants of MSCs bygradient centrifugation, and conducted microarray analysisto determine the miRNA expression profile of MSC-EXO(Ti et al., 2015). Following probe screening and data normal-ization, we found 42 significantly differentially expressed

miRNAs compared to in human fibroblast-derived exosomes(FIB-EXO, Figure 1). Among 15 up-regulated miRNAs,three (miR-21, miR-146a, and miR-181) displayed the mostsignificant and highest expression in MSC-EXO (data notshown). Next, we performed bioinformatics prediction to de-termine potential downstream targets of miR-21, miR-146a,and miR-181. According to the Reactome Database, targetsof these three specific miRNAs were statistically enrichedin genes and proteins participating in cellular developmentand function, innate immune response, inflammation, andcell signaling. Particularly, the Toll-like receptor (TLR)pathway and IL-6 pathway have been shown to be importantcellular pathways fundamentally required for activation ofthe immune system and orchestration of the inflammatoryprocess after tissue damage.Given the essential role of the miRNA processing machin-

ery in immune cell development and inflammatory responses,we hypothesized that these three specific miRNAs in MSC-EXO could modulate the expression of inflammation-relatedgenes, which may reduce delayed inflammation and enhancewound healing. However, little is known about how and towhat extent these miRNAs function in the immune stimula-tory program of MSCs, which is an important issue for po-tential therapeutic molecule discovery to coordinate uncon-trolled inflammation. We reviewed their biological activitiesinteracting with inflammatory cells and directly regulatingintracellular regulatory mechanisms or affecting the cellularphenotype in the resolution of wound inflammation.

miR-21

miR-21 can be selectively packaged from original cellsinto exosomes and acts as a rheostat to modulate immunecell function and the inflammatory response. Pieters etal. demonstrated that extracellular vesicles, including exo-somes, which were isolated from commercial bovine milk,could induce Th17 differentiation in murine splenocytes,and miR-21 was present in the immunoregulatory cargocarried by these extracellular vesicles (Pieters et al., 2015).In addition, data analyses of the human MSC secretomeconfirmed that miR-21 protects MSCs under serum-de-prived conditions and can trigger key biological functionsin recipient cells (Nie et al., 2011). Efficient efferocytosisinduces potent anti-inflammatory and immunosuppressivemechanisms that are required for the timely resolution ofinflammation. Notably, miR-21 is efferocytosis-induciblein macrophages, subsequently promoting efferocytosis pro-gression. In the regulatory loop, miR-21 silences PTEN andGSK3β, dampens NFκB activation, and promotes c-Jun/AP1activities, which control the inflammatory response and pro-mote wound healing (Das et al., 2014). Furthermore, miR-21is instrumental in the regulation of macrophage phenotypeand inflammation ablation for efficient stem cell-dependenttissue repair.  In  response  to  bacterial  infections,  miR-21

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Figure 1         Analysis of miRNA expression profiling in MSC-EXO. A heatmap was generated after supervised hierarchical cluster analysis. Differential miRNAexpression is shown in red (upregulation) versus green (downregulation) intensity (MSC-EXO versus FIB-EXO, 2-fold change, P<0.05).

leads to NFκB activation in pro-inflammatory macrophages,thus promoting both inflammation and the expression of anti-inflammatory genes. It then depresses PTEN in anti-inflam-matory macrophages, resulting in AKT activation to cause in-flammation alleviation and wound healing (Perdiguero et al.,2011). Hence, we suggest that miR-21 is a highly interest-ing and significant player in downstream inflammatory path-ways and post-host immune responses mediated by diverseimmune cells; the expression of miR-21 in MSC-EXO maybe involved in the modulation of the inflammatory responseduring tissue repair.

miR-146a

miR-146a was previously shown to be highly expressed inmultiple types of adult stem cells. Furthermore, miR-146amay play a role in mediating short-term memory in immunesystem cells and MSCs after environmental stimulation.When MSCs migrate to the inflammatory microenvironmentin injured tissues, they possess a “short-term memory” fordanger signals and display enhanced therapeutic immunoreg-ulation efficacy by inducing stimulus-responsive regulatorymolecules, such as miR-146a (Liu et al., 2016). Saba et al.suggested that in response to inflammatory cues, miR-146acan function as a key regulator of the innate immune re-sponse to arrest the expression of several pro-inflammatoryfactors, including TNF-α, IL-6, and IFN-γ, and direct the in-

flammatory response (Saba et al., 2014). miR-146a can alsoprotect the functional capabilities and longevity of murinehematopoietic stem cells against prolonged inflammation;these cells are critical for an adequate inflammatory andimmune response in healthy individuals (Zhao et al., 2013).In addition, miR-146a regulates not only the acute T cell re-sponse but also chronic T cell hyper-inflammatory responseand development of T cell-associated autoimmunity. This isachieved by repressing NFκB activity and monitoring the Tcell response to antigen stimulation during T cell activation(Meisgen et al., 2014). Etzrodt et al. showed that miR-146amay regulate monocyte subset population dynamics. In vivoenhancement of miR-146 transcription in macrophages andmonocytes can attenuate monocyte/macrophage activationand inhibit pro-inflammatory macrophage responses to sup-press NFκB-mediated inflammation (Etzrodt et al., 2012).Thus, MSC-shuttled exosomal miR-146a may have a diverseand critical role in limiting an excessive inflammatory reac-tion, and therefore represent a future therapeutic target forexogenous modulation of wound inflammation.

miR-181

Experiments have shown that miR-181 plays an importantrole in the development, differentiation, and activation of Tlymphocytes, B lymphocytes, and natural killer cells (Chenet al., 2004; Beaulieu et al., 2013). The immune system

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mounts rapid and specific defense responses and developsand maintains a steady microenvironment; if deregulated,this can result in decreased regenerative capacity and variouspathological disorders, including defects in host-pathogeninteractions, autoimmune diseases, or chronic inflammation.Thus, miR-181 may provide excellent spatio-temporal mon-itoring of immune cells, modulate the strength and thresholdof immune signals under physiological and pathological con-ditions, and switch outcomes on immune responses for tissuehomeostasis. When miR-181 is deficient in a specific tissuein mice, conventional T cell and natural killer T cell devel-opment were perturbed and PI3K signaling was impaired,which results from the cumulative effect of increased PTENexpression (Henao-Mejia et al., 2013). Dan et al. suggestedthat miR-181 upregulation is the primary host protectivemethod against endotoxin shock, as it can switch the im-mune status from hyperinflammation to endotoxin toleranceby quickly decreasing inflammatory cytokine expressionwithout influencing the expression of anti-inflammatorycytokines (Dan et al., 2014). In an experimental neuroin-flammatory model, miR-181 was found to be necessary forthe reactive phenotype of astrocytes to inflammatory settingsby reprogramming the transcriptional profiles of general celldifferentiation and stress responses (Hutchison et al., 2013).These results clearly illustrate that miR-181 plays a centralrole in anabolic metabolism in immune cells and fine-tunestheir immunological functions to prevent overwhelminginflammation during tissue regeneration.

UNIQUE MICRORNA EXPRESSIONIN MSC-EXO CONTRIBUTES TO THERESOLUTION OF WOUND INFLAMMATION

Increasing data have shown that MSC-EXO have specific bi-ological functions for modulating the immune and inflamma-tory response and repairing tissue damage. The manipulationof genetic elements using selective exosomal regulation mayhave fully or partially penetrant effects on pathological con-ditions at the cellular and systemic levels. Blazquez et al.showed that MSC-EXO have an inhibitory role in the differ-entiation, proliferation, and activation of T cells and IFN-γrelease during the treatment of inflammation-related diseases(Blazquez et al., 2014). These observations suggest that spe-cific therapeutic miRNA populations in MSC-EXO reshapethe immunomodulatory strength of MSCs to mediate targetimmune cell activation, phenotypic modification, and repro-gramming of cell function. Moreover, in our study, bioinfor-matic approaches indicated that specific miRNAs shuttled byMSC-EXO have complex pleiotropic effects on many aspectsof inflammation. These miRNAs are predicted to target im-mune and inflammatory response genes, including transcrip-tion factors, co-factors, and chromatin modifiers. In addition,critical proteins involved in regulating inflammation, such as

TLRs and IL-6, have been suggested to act as links betweenMSC-EXO and inflammatory pathway activation in immunecells. Therefore, studies of the immune signals andmechanis-tic pathways regulated by miR-21, miR-146a, and miR-181may enable better modulation of inflammation and advancedmethods for stem cell-mediated tissue repair.

TLR signaling pathway

TLRs are a class of membrane-bound pattern recognitionreceptors that are responsible for recognizing particularpathogen-associated molecular patterns from infectiouspathogens. The immune system mainly detects and iden-tifies pathogenic molecules via TLRs then triggers varioustranscription factors, leading to strong production of pro-in-flammatory cytokines (Sabouri et al., 2014; Helley et al.,2015). Inappropriate quantities or qualities of TLR ligandsor aberrant response to TLR activation have been observed invarious impaired inflammatory conditions. miRNA, whichinhibits protein expression through mRNA degradation ortranslational repression, can be used to precisely regulate theimmune system and immune cell activity. Therefore, specificmiRNAs in MSC-EXOmay strictly modulate TLR-signalingpathways to prevent excessive inflammation and achievea balanced microenvironment. For example, miR-146a isa regulatory element in keratinocyte innate immunity thatsuppresses the expression of a large number of inflammatorygenes under homeostatic conditions and serves as a potentnegative feedback regulator of the TLR proinflammatorypathway. Furthermore, miR-181 directly binds to the 3′untranslated region of IL-8, and represses its expression inhuman fibroblasts. Thus, upregulation of miR-181 may beassociated with the homeostatic response to inflammatorystimuli such as IL-8 by TLR pathway activation (Galicia etal., 2014).Once activated, the TLR pathway acts through different

intracellular signaling cascades and leads to activation ofNFκB and TRIF-dependent signaling, resulting in cytokine,chemokine, and cell adhesion molecule induction. Evi-dence is accumulating that miRNAs function as importantimmunomodulators to fine-tune the TLR-induced NFκBsignaling pathways and downstream consequences. miR-21was induced by the TLR/NFκB pathways in LPS priminghuman peripheral blood mononuclear cells, in turn, repress-ing the NFκB pathway and upregulating IL-10 production(Sheedy et al., 2010). Feng et al. found that miR-21 inhibitslipid-laden foam cell formation and inflammatory responsesin LPS-stimulated macrophages through the TLR4-NF-κBpathway (Feng et al., 2014). Hence, we hypothesize that par-ticular miRNAs in MSC-EXO create a regulatory feedbackto monitor certain TLR-activated transcription factor-depen-dent pathways and timely decrease and/or terminate TLRsignaling by targeting the expression of critical signalingcomponents.

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IL-6 signaling pathway

IL-6 is a pleiotropic cytokine that regulates multiple bi-ological processes, including acute phase responses, cellregeneration, inflammation, and immune responses. As apro-inflammatory soluble factor, IL-6 produced by mono-cytes-macrophages represents a key molecule in the induc-tion and maintenance of delayed inflammation during RAprogression. Some evidence suggests that IL-6 compromisestissue repair by shifting acute inflammation into a morechronic profibrotic state induced by Th1 cells as a conse-quence of recurrent inflammation (Fielding et al., 2014). Inall cases tested, blockade of IL-6 by specific miRNAs inMSC-EXO may be a useful therapeutic measure for woundinflammation. For example, in a mathematical inflammationmodel, miR-146 and miR-21 significantly controlled thecoupled inflammatory reactions by fine-tuning the activationdynamics of the key mediators of IL-6 (Xue et al., 2013).After LPS exposure, increased miR-181 may be involved indecreasing IL-6 expression, which may be also an importantregulatory mechanism for controlling the pro-inflammatoryimmune response and induction of endotoxin tolerance(Zhang et al., 2015).In the classic signaling pathway, IL-6 binding to the

membrane-bound IL-6 receptor (IL-6R) is followed by ho-modimerization of IL-6R with its signal-transducing elementgp130 and initiation of the phosphorylation of the tran-scription factors STAT3. It has been demonstrated that theIL-6-gp130-STAT3 signaling axis is necessary for the orches-tration of inflammatory processes in animal models (Hirano,2010). The identification of novel upstream modulators ordownstream targets of the IL-6/STAT3 pathway will provideinsight into the involvement of altered miRNA expressionin the progression of chronic inflammation. In RA patients,the expression levels of miR-21 were significantly lower andaccompanied by increased STAT3 expression and activation(Dong et al., 2014). Moreover, Iliopoulos et al. found thatmiR-21 and miR-181 are rapidly and dramatically regulatedduring cellular transformation. A transient inflammatory sig-nal triggers the inflammatory feedback loop involving IL-6,STAT3, miR-21, and miR-181 and induces an epigeneticswitch that links inflammation to cancer; the transformedstate can be interrupted by any genetic or environmentalchange affecting the factors of the inflammatory feedbackloop (Iliopoulos et al., 2010). These complex mechanismsprovide a paradigm for molecular target therapy in which akey process of disease progression involves miRNA-inducedchanges in response to an inflammatory signal.

PERSPECTIVES AND FINAL REMARKS

In this review, we examined the miRNAs profiling inMSC-EXO and explored the impacts of selected miRNAs

(miR-21, miR-146a, and miR-181) on inflammatory re-sponses and tolerance at the molecular, cellular, and systemiclevels. miRNA expression may be turned on or off at thetranscriptional level upon ligand stimulation and can haveeither positive or negative effects on the expression of sig-naling components that impact the development or functionof different target cells. In some inflammatory disorders,studies have suggested that prominent up-regulation ofmiRNAs, such as miR21, is specifically involved in modu-lating TLR associated NFκB signaling networks activatedby the pathological microenvironment (Kalla et al., 2015).Conceivably, miR146a is differentially expressed in variousautoimmune diseases including rheumatoid arthritis andmultiple sclerosis and its regulation may influence the de-velopment or prevention of autoimmunity (Dai and Ahmed,2011). As exosomes naturally transfer RNA moleculesbetween cells, this property may be useful in gene therapy,in which a vector is used to deliver therapeutic nucleic acidsto the patient’s target cells. Researchers have reported thatexosomes can deliver synthetic miR-143 and are a poten-tially efficient and functional delivery system (Shimbo et al.,2014). These examples suggest that MSC-EXO may balancethe dysregulated inflammatory condition without causingsignificant toxicity through specific miRNAs and can be usedas efficient vehicles in RNA-based therapeutic strategies.Such efforts will ultimately reveal the immunoregulationfunction of miRNA and evaluation of whether their releasevia MSC-EXO is involved in the resolution of chronic in-flammation and orchestrating wound healing.

Compliance and ethics               The author(s) declare that they have no conflictof interest.

Acknowledgements          This work was supported by the National BasicScience and Development Program (2012CB518103, 2012CB518105),National High Technology Research and Development Program of China(2013AA020105, 2012AA020502), and National Natural Science Founda-tion of China (81121004, 81501682, 81230041).

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